By interrelating in vitro, experimental animal and clinical studies we propose to examine platelet and endothelial mechanisms underlying the development of acute and chronic vascular disease, the associated thrombotic consequences and the therapeutic effects of modifying platelet and endothelial behavior by selected pharmacologic agents. Cultured human endothelial cells will be used to study 'injury' and repair in vitro. We propose to examine desquamative and functional injury produced by endotoxin, blood cell-derived factors, hyperlipoproteinemia, antibody, homocysteine, anoxia and selected patient blood samples. In this context the studies of altered endothelial function will include uptake and release of platelet factor 4 and platelet derived growth factor, as well as the modulation of PGI2 and endothelial derived mitogen synthesis by endothelial cells. Experimental baboon models will be used to characterized platelet activation, accumulation and release of constituents in acute desquamative injury induced in baboons by infusing homocysteine. 111In platelets will be used to assess local accumulation and rates of destruction and 14C-serotonin survival will be used to detect selective dense granule release. Plasma platelet factor 4 levels will be used as an indicator of alpha granule release. The mechanism of endotoxin-induced desquamation, platelet activation and hypotension will also be studied in the baboon model by using inhibitor studies with drugs or epi-PGI1 antisera. The baboon model of arterial thromboembolism will be used to evaluate the antithrombotic efficacy of PGI2 and the interactive mechanism of ASA, dipyridamole, sulfinpyrazone and PGI2 on platelet thrombus formation. Patients with atherosclerotic vascular disease will be studied to evaluate platelet activation, release of dense bodies and alpha granules, thrombotic accumulation and the potential for pharmacologic modification using selected drugs that alter platelet and endothelial behavior.